The peripheral taste organ is an excellent sensory system for understanding the interactions between the nervous system and the target tissues it innervates. We have shown that two members of the neurotrophin family, Brain-derived neurotrophic factor (BDNF) and Neurotrophin 3 (NT-3) play important roles in the innervation of the developing tongue. BDNF null-mutated mice exhibit specific impairments related to innervation and development of the gustatory system whereas NT-3 null mice have deficits in their lingual somatosensory innervation. Knockout mice for another neurotrophin, neurotrophin 4 (NT-4), also exhibit gustatory deficits in the anterior part of the tongue during postnatal development. Null-mutation of a gene provides an excellent system to determine the functions of the gene product. However, the deficits in single knockout mice could be masked by the presence of closely related factors. To study the specificity of neurotrophin function, it is important to exclude compensatory mechanisms due to the synergy of the function by other family members. To address this, we have crossbred existing neurotrophin knockout mice to examine the specificity of a single neurotrophin in the peripheral taste system by comparing the phenotype of the double neurotrophin knockout mice to single neurotrophin knockout mice. There is a rapid turnover of taste receptor cells that necessitates continuous rewiring of existing nerve fibers and formation of new synapses. BDNF is expressed in the adult taste buds and might participate in this process. To address this, we have used a well-characterized alpha-gustducin promoter and have generated a novel transgenic mouse model in which BDNF is over-expressed by taste cells. Our preliminary results indicate that Gust-BDNF mice are viable and BDNF is over-expressed in taste buds. We hypothesize that site-specific over-expression of BDNF will result in functional changes in the taste system. Analysis of Gust- BDNF mice will help to elucidate the roles of BDNF in the adult taste system. The proposed research will contribute new data on key issues in taste neurobiology. Unique transgenic animals are used with double neurotrophin knockout phenotypes and taste cell-specific over-expression of BDNF in taste buds that provide novel methods for understanding the roles of neurotrophins in taste biology.